Legumain (Asparaginyl endopeptidase) (LGMN (AEP))

Asparaginyl endopeptidase (AEP), also known as legumain or delta-secretase, is a highly specific cysteine protease that hydrolyzes peptide bonds on the C-terminal side of asparagine and aspartate residues (Song, 2022). While it is primarily localized within the acidic environment of lysosomes where it facilitates antigen processing and the maturation of other proteases, its upregulation and mislocalization are linked to various pathologies (Zhang et al., 2017). In neurodegenerative diseases like Alzheimer's and Parkinson's, AEP acts as a secretase that cleaves Tau, amyloid precursor protein (APP), and alpha-synuclein into neurotoxic, aggregation-prone fragments (Wikipedia). In oncology, AEP is overexpressed in several solid tumors and is secreted into the tumor microenvironment to promote tissue invasion and metastasis (Yang et al., 2020). Consequently, AEP is an emerging therapeutic target, with research focusing on the development of small molecule inhibitors to treat neurodegeneration and AEP-activated prodrugs designed to target cancer cells selectively.

Other names

Asparagine endopeptidaseDelta-secretasePRSC1CitvacProteinase BHemoglobinaseVicilin peptidohydrolaseBean endopeptidaseCysteine protease 1

Direct inhibition of proteolytic activity to prevent the cleavage of pathogenic proteins into toxic fragments; enzymatic activation of AEP-sensitive prodrugs specifically within the acidic tumor microenvironment to release cytotoxic payloads.